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Tsukushi, small leucine-rich proteoglycan (TSKU) is a class IV extracellular matrix proteoglycan protein encoded by the TSKU gene, predominantly found in the extracellular space and involved in regulation of multiple developmental and metabolic processes. It directly binds and antagonizes growth factors and signaling molecules such as TGF-β and components of the Wnt pathway, modulating cell fate, differentiation, bone and cartilage growth, cholesterol homeostasis, wound healing, hair follicle cycling, and neural stem cell differentiation. Tsukushi also influences RNA splicing networks and gene regulation, particularly in neural stem cells and developing tissues. Dysfunction or altered expression of tsukushi is implicated in developmental disorders (including hydrocephalus), certain cancers, and abnormalities in bone and tissue growth, but to date, there are no drugs specifically targeting the protein, though its pathway regulatory roles render it of high interest for possible future therapeutic targeting.
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